Triacylglycerols in adipocyte lipid storage droplets are the primary energy reserves in animals, and fatty acids are marshaled by a cAMP- dependent protein kinase (PKA)-mediated process. PKA phosphorylates both hormone-sensitive lipase (HSL), the rate-limiting enzyme of lipolysis, and perilipins, proteins that coat the surface of lipid droplets. By an analogous system, steroid hormone synthesis is initiated by the hydrolysis of cholesteryl esters (CE). We find that adrenal cortical and Leydig cells express perilipins, which are located exclusively at the surface of CE droplets. Murine adipocytes and steroidogenic cells express 4 perilipins (A, B, C, D); the A species is the most abundant in all cells, whereas the C species is relatively abundant in steroidogenic cells but rare in adipocytes. Given the parallels between the modes of lipid hydrolysis in adipocytes and steroidogenic cells, the finding of perilipins in both types of cells supports the idea that perilipins play a role in lipid metabolism. Experimental evidence supports our proposal that translocation of HSL to lipid droplets is a critical event in lipolysis. We find by immunofluorescence that HSL is distributed diffusely in the cytoplasm of unstimulated adipocytes; upon stimulation, HSL migrates rapidly to lipid droplets. Test systems have been developed to further dissect the lipolytic reaction and to examine the targeting of perilipins to lipid droplets. These include 3T3-L1 adipoblasts stably transfected with both sense and antisense perilipin cDNA constructs as well as adrenal cortical cells transfected with cDNA constructs bearing epitope tags at both N- and C-terminal regions of perilipin A. The products of all such constructs localize to lipid droplets. Interestingly, adipoblasts containing the sense perilipin constructs fail to differentiate, but contain perilipin associated, paradoxically, with TG droplets suggesting a role for perilipins in lipid packaging. Cytokines that have been implicated in disease-associated cachexia are TNF, IL-6, and LIF. We have found that these agents increase the tyrosine phosphorylation and activity of MAP kinases, but that IL-6 and LIF also increases the tyrosine phosphorylation of several cytosolic proteins. Two such proteins of 90/92 kDa appear to be STAT3, transcription factors that translocate to the nucleus upon phosphorylation. These events may underlie actions that contribute to cachexia, such as reduced expression of lipoprotein lipase.